Effects of tobacco smoke on the gene expression of the Cyp1a, Cyp2b, Cyp2e, and Cyp3a subfamilies in mouse liver and lung: relation to single strand breaks of DNA.
Cigarette smoking is a worldwide health problem and is the greatest risk factor for lung cancer. By activating procarcinogens, hepatic and extrahepatic cytochromes P450 can participate in lung carcinogenesis. Tobacco smoke contains numerous cytochrome P450 inducers, substrates, and inhibitors. In the present study we investigated, in male NMRI mice, the effects of cigarette smoke on hepatic and pulmonary cytochrome P450 expression and their possible role in the induction of DNA lesions such as DNA single strand breaks (SSB). Hepatic and pulmonary mouse cytochrome P450 isozymes involved in carcinogenesis (Cyp1a, 2b, 2e, 3a) were differently induced by cigarette smoke. Cyp2e1 mRNA was dramatically enhanced (12.7-fold increase) while Cyp2b10 mRNA remained unchanged and Cyp1a1 was decreased or not detected. Cyp3a protein and mRNA were not detected in lung, suggesting that this isozyme is not expressed in mouse pulmonary tissue. The SSB of DNA increased in lung and liver treated mice. In contrast no modification was observed in lymphocytes that barely expressed cytochromes P450. Cimetidine and propylene glycol reduced SSB of DNA induced by smoking in liver and lung cells. The inhibition (-70%) observed in lung following treatment by propylene glycol, a CYP2E1 inhibitor, suggested that this isozyme is at least in part involved in pulmonary DNA damage induced by tobacco smoke. The high concentration of CYP2E1 function and regulation in mammals suggests that this protein could be involved in pulmonary carcinogenesis in human smokers.
Villard
P H
PH
Faculté de Pharmacie, Université de la Méditerranée, 27 Bd. Jean Moulin, Marseille Cedex 5, 13385, France.
Seree
E M
EM
Re
J L
JL
De Meo
M
M
Barra
Y
Y
Attolini
L
L
Dumenil
G
G
Catalin
J
J
Durand
A
A
Lacarelle
B
B
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002263:Carboxyhemoglobin / Q000032:analysis; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D015786:Cytochromes b5 / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage; D004277:DNA, Single-Stranded; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology*; D008175:Lung Neoplasms / Q000209:etiology; D008297:Male; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D004277:DNA, Single-Stranded; D007527:Isoenzymes; D012333:RNA, Messenger; D014028:Tobacco Smoke Pollution; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D002263:Carboxyhemoglobin; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating